Keratinocyte-associated protein 3 plays a role in body weight and adiposity with differential effects in males and females

Szalanczy, Alexandria M; Goff, Emily; Seshie, Osborne; Deal, Aaron; Grzybowski, Michael; Klotz, Jason; Key, Chia-Chi Chuang; Geurts, Aron M.; Woods, Leah C. Solberg

doi:10.3389/fgene.2022.942574

Cited by 8 publications

(35 citation statements)

References 37 publications

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“…In the current study, there were no differences in the adiposity measures between WT and KO females, contradicting our previous results [13]. Upon closer inspection of the data, we determined that in Study 2 WT rats consumed a greater amount of food, which led to an increased body weight and fat mass-WT rats had increased in size without a corresponding change in KO rats.…”

Section: Discussioncontrasting

confidence: 99%

“…At euthanasia, there were no differences in RetroFat mass nor ParaFat mass between WT and KO females (Table 3). Though these data contradict our previous findings [13], the adiposity and metabolic measures do support the lack of body weight differences seen between WT and KO females in this study. There were also no noteworthy differences in body size or non-adipose organ weights between WT and KO rats (Table 4).…”

Section: No Difference In Adiposity Measures Between Wt and Ko Ratscontrasting

confidence: 95%

“…Krtcap3 is also highly expressed in the gastrointestinal tract of the rats, which supports our previously suggested role along the gut-brain axis [13]. The gut-brain axis has repeatedly been linked to behavior in preclinical and clinical models, germ-free status can negatively impact basal and stimulated HPA activity [49],…”

Section: Tissue Expression Supports a Possible Role Of Krtcap3 In Str...supporting

confidence: 84%

“…As previously described, we generated a whole-body in vivo Krtcap3 knock-out (KO) on the Wistar-Kyoto (WKY/NCrl; RGD_1358112) inbred rat strain (WKY-Krtcap3 em3Mcwi ) [13]. In 2019, we established a breeding colony at Wake Forest University School of Medicine (WFSoM).…”

Section: Animalsmentioning

confidence: 99%

“…Specifically, we developed a Krtcap3 knock-out (KO) rat model on the inbred Wistar-Kyoto background strain. We showed that KO rats had increased body weight in both sexes relative to wild-type (WT) rats, and that female KO rats had increased eating and fat mass relative to WT rats [13]. Despite this validation, very little is known about the underlying molecular mechanisms of how Krtcap3 impacts adiposity.…”

Section: Introductionmentioning

confidence: 99%

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Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated withKrtcap3

Szalanczy

Giorgio

Goff

et al. 2023

Preprint

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We previously identified Keratinocyte-associated protein 3, Krtcap3, as an obesity-related gene in female rats where a whole-body Krtcap3 knock-out (KO) led to increased adiposity compared to wild-type (WT) controls when fed a high-fat diet (HFD). We sought to replicate this work to better understand the function of Krtcap3 but were unable to reproduce the adiposity phenotype. In the current work, WT female rats ate more compared to WT in the prior study, with corresponding increases in body weight and fat mass, while there were no changes in these measures in KO females between the studies. The prior study was conducted before the COVID-19 pandemic, while the current study started after initial lock-down orders and was completed during the pandemic with a generally less stressful environment. We hypothesize that the environmental changes impacted stress levels and may explain the failure to replicate our results. Analysis of corticosterone (CORT) at euthanasia showed a significant study by genotype interaction where WT had significantly higher CORT relative to KO in Study 1, with no differences in Study 2. These data suggest that decreasing Krtcap3 expression may alter the environmental stress response to influence adiposity. We also found that KO rats in both studies, but not WT, experienced a dramatic increase in CORT after their cage mate was removed, suggesting a separate connection to social behavioral stress. Future work is necessary to confirm and elucidate the finer mechanisms of these relationships, but these data indicate the possibility of Krtcap3 as a novel stress gene.

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Section: Discussioncontrasting

confidence: 99%

Section: No Difference In Adiposity Measures Between Wt and Ko Ratscontrasting

confidence: 95%

Section: Tissue Expression Supports a Possible Role Of Krtcap3 In Str...supporting

confidence: 84%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated withKrtcap3

Szalanczy

Giorgio

Goff

et al. 2023

Preprint

Self Cite

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Large-scale cross-ancestry genome-wide meta-analysis of serum urate

Cho,

Kim,

Kim

et al. 2024

Nat Commun

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Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

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Chronic Stress Increases Adiposity and Anxiety in Rats with Decreased Expression ofKrtcap3

Szalanczy,

Fitzpatrick,

Beeson

et al. 2023

Preprint

Self Cite

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We previously identified Keratinocyte-associated protein 3, Krtcap3, as a novel adiposity gene but subsequently found that its impact on adiposity may depend on environmental stress. To more thoroughly understand the connection between Krtcap3, adiposity, and stress, we exposed wild-type (WT) and Krtcap3 knock-out (KO) rats to chronic stress then measured adiposity and behavioral outcomes. We found that KO rats displayed lower basal stress than WT rats under control conditions and exhibited the expected responses to chronic stress exposure. Specifically, stress-exposed KO rats gained more weight, consumed more food when socially isolated, and displayed more anxiety-like behaviors relative to control KO rats. Meanwhile, there were minimal differences between control and stressed WT rats. At study conclusion stress-exposed KO rats had increased corticosterone (CORT) relative to control KO rats with no differences between WT rats. In addition, KO rats, independent of prior stress exposure, had an increased CORT response to removal of their cage-mate (psychosocial stress), which was only seen in WT rats when exposed to chronic stress. Finally, we found differences in expression of the glucocorticoid receptor, Nr3c1, in the pituitary and colon between control and stress-exposed KO rats that were not present in WT rats. These data support that Krtcap3 expression affects stress response, potentially via interactions with Nr3c1, with downstream effects on adiposity and behavior. Future work is necessary to more thoroughly understand the role of Krtcap3 in the stress response.

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Keratinocyte-associated protein 3 plays a role in body weight and adiposity with differential effects in males and females

Cited by 8 publications

References 37 publications

Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated withKrtcap3

Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated withKrtcap3

Large-scale cross-ancestry genome-wide meta-analysis of serum urate

Chronic Stress Increases Adiposity and Anxiety in Rats with Decreased Expression ofKrtcap3

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